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1、OrganicProcessResearch&Development2005,9,956-961FullPapersAComparisonofCatalyststoPromoteImidazolideCouplingsIncludingtheIdentificationof2-Hydroxy-5-nitropyridineasaNew,Safe,andEffectiveCatalystPeterJ.Dunn,*,²WilfriedHoffmann,²YingKang,²,³JohnC.Mitchell,³andMartinJ.Snowden³DepartmentofChemica
2、lResearchandDeVelopment,PfizerGlobalResearchandDeVelopment,Sandwich,KentCT139NJ,UnitedKingdom,andMedwaySciences,UniVersityofGreenwich,MedwayCampus,Chatham,KentME44TB,UnitedKingdomAbstract:Scheme1Fivecatalystswerecomparedwithrespecttotheirsafetyandcatalyticeffectivenessforpromotingimidazolidec
3、ouplings.Reactionrateenhancement,shocksensitivity,anddifferentialscanningcalorimetry(DSC)datawereconsideredinthisanalysis.6-Chloro-1-hydroxybenzotriazole,whichhasbeendescribedintheliteratureasasafecatalyst,wasfoundtobeshocksensitive.2-Hydroxy-5-nitropyridineisanewcatalystforthistypeofreaction
4、andwasfoundtobesafe,effective,readilyavailable,andsimilarinpricetothatofthe1-hydroxybenzo-triazole,acommoncatalystforpromotingacylationreactions.Scheme2IntroductionTheuseofN,N1-carbonyldiimidazole(CDI)asacouplingagentforamidebondformationhasrecentlybeenappliedtothelarge-scalesynthesisofanumbe
5、rofpharmaceuticalproducts,forexample,sildenafil,1darifenacin,2andsunitinib.3Inadditionasurveyof128chemicalprocessesrecentlydevelopedbyAstraZeneca,GlaxoSmithKline(GSK),andPfizerrevealedthatCDIwasthethirdmostcommonreagentOnefactorinfluencingtheincreaseduseofCDIonalargeusedforN-acylationreaction
6、sandwasusedin9outof84scaleisitsrelativelylowprice(around$8/molforalarge-examples.4Theadvantagesarethatthebyproducts,carbonscalepurchase).AlthoughCDIismoreexpensivethandioxideandimidazole,areinnocuousandthattheevolutiontraditionalamide-formingreagents,suchasthionylchlorideofcarbondioxideinform
7、ingtheimidazolide1providesaandisobutylchloroformate,insomecasesthehighyieldsdrivingforceforthereaction5,6(Scheme1).Inadditiontheandcleanenvironmentalconditionscanjustifyitsuse.imidazolebyproductcanberemovedbyanacidicwash2orAdisadvantageofCDIi
